2, 4-diamino-5-benzyl pyrimidines



Patented Nov. 10, 1953 2,4-DIAMINO-5-BENZYL PYRIMIDINES George H. Hitchings, Tuckahoe, and" Elvira A..

Falco, New Rochelle, N. Y., assignors to Burroughs Wellcome & 00. (U. S. A) Inc., Tucka hoe, N; Y., a corporation of'New'Yorlc No Drawing. Application'June27;;1951; Serial No. 233,951-

6.Claims; (Cl.Mil-4256.4)v

The present invention relates to a; new class of 5-benzyl-2,4-diaminopyrimidines of the formula wherein R is'a radical-selected from the class m consisting of the lower alkoxy radicals and the phenyl radical, R=is a radical selected from the class consisting of the lower alkoxy radicals "and hydrogen and R is selected from the class consisting of hydrogen, and the halogens and the nitro-groups when R is alkoxyl; This applica.-.- tion is a continuation-in-partlof our co-pending U.- S. application 161,256, filed May 10, 1950, now Patent No. 2,624,732.

These substances are characterized byexceptionally high antibacterial activities which. fit them for surface application towounds. Certain of. them also maintain their activity in the pres-- encetof body fluids: and may therefore-be of value: for the treatment ofsystemic' infections.

The preparationof these substances involves the synthesis of a suitable hydrocinnamic ester (I), which is formylated (IDand condensed with guanidine to give a:2-amino-4-hydroxypyrimi+ dine (III). Subsequent conversion to the diamino compound takes place readily by chlorination and amination, or. by thiationv and amination as described in our cognateapplications, Serial Numbers 33,677 and'33,678 both" now abandoned, in conjunction with the method of U. S. Patent No. 2,415,793 to Hitchings and Elion.

Asuavariant; a .hydrocinna'mi'c nitrile may be formyla-te'd. and theiresultant .hydroxy'. methylene hydrocinnamicfmtrile may: be. converted: to" an alkoxymethylene derivative (enol-ether) which is then cyclized=withiguanidinei directlyito. give the desired 2,4diamino-5-benzyl pyrimidine.

This alternative synthesis follows thecourse shown below;

N mom onc- 8." RCHzCHzCN+HCOOEt Rome CN(or ROHzCHCN).

l C E'rNz or "HO O E t neg-d ns: RCHz- -CN' (wherein CHR is the 5-benzyl group of For mulaI).

The following examples will serve to" illustrate the teachings of our discovery, but are not to be regardedaslimitingtheinvention except as defined in the accompanying claims.

EXAMPLE-1 zg4 diami1io- 5- (2 '3 -dimethoxybenzyl) pyrimidine AFZT amino- 4 hydromy. 5 (2"3' dimethoxybenzyl) pyrimidine-To 90.4 g. ofethyl- 2,3-dimethoxyhydrocinnamate (0.38 mole) was added30g. of ethyl :formate (0.40 mole) and this was poured onto 8.7 g. of sodium wire (0.38 male) in 500 m1. of sodium dried ether. After standing .72thours the ether was evaporated off and the guanidine from 37. g of guanidine hydrochloride (0.38 mole) and 8.7 g. of sodi-um'in 300ml. of:

ethanol was filtered into the :reaction mixture.

The mixture was refiuxedwforfs hours on the" .;steam bath, poured into about 2 liters of water and neutralized with acetic acid. The crude precipitate was collected;.it-weighed 25 g. after washing with water and ether.

B. 15 g. (0.57 mole) I were refluxed with1;50 ml. of phosphorous oxychloride for cne-h'alf hour;

The excess reagent was taken off in vacuo and the residue decomposed by-pourin'g over 200 g. of icea- This was made alkaline-with ammonium hydrox me to pH 9 and filtered. The crude chlorocompound was sucked 'dry and placed in abomb with 200 ml. of saturated (10) ethanolic ammonia. The bomb was heated 16 hours at a temperature of 160, opened and the alcohol evaporated on the steam bath. The residue was taken up in dilute acetic acid and precipitated by the addition of sodium hydroxide to pH 10. The resulting precipitate was filtered and recrystallized from 95 percent ethanol to give 5.7 g. of white crystalline material having an M. P. of 193197.

EXAMPLE 2 2,4-diamino--(3'4-dimethoasybenzyl) pyrimidine A. 2 amino 4 hydrorry 5 (3'4' dimethoxybenzyl) pyrimidine. This compound was prepared in the same manner as Example l-A by the addition of 60 g. of ethyl-34-dimethoxyhydrocinnamate and 20.6 g. of ethyl formate to 5.8 g. of sodium Wire in ether to give the crude sodium formyl compound which was condensed with 24.2 g. of guanidine hydrochloride in 5.8 g. of sodium in alcohol. The crude amino-hydroxy compound thus obtained melted at 230-237.

B. The preparation of the 2,4-diamino-5-3'4'- dimethoxybenzyl) pyrimidine.-This compound was prepared in the same manner as Example l-B. The amino-hydroxy compound was con verted to the amino-chloro compound by means of phosphorous oxychloride, the crude chloro compound was then heated with alcoholic ammonia at 150 to give 2,4-diamino-5-(34-dimethoxybenzyl) -pyrimidine. This melts at 224-229" after recrystallization by solution in dilute acetic acid and precipitation with alkali at pH 10.

EXAMPLE 3 2,4-diamino-S-p-methoccybeneylpyrimidine The aminohydroxy compound was prepared in the usual manner from ethyl-p-methoxy-hydrocinnamate. It was converted by means of phosphorous oxychloride and subsequent amination to 2,4-diamino-5-p-methoxybenzylpyrimidine melting at 198-202", in white micro needles from 95 percent ethanol.

EXAMPLE 4:

2,4 diamino 5-(3'ethoacy 4' methozrybenzyl) pyrimidine EXAMPLE 5 2,4-diamin0-5-(34'-diethomybenzyl) pyrimidine A. Preparation of 2-amino-4-hydroscy-5-(3%!- diethoxybeneyl) pyrimidine.From '70 g. (0.263 mole) of ethyl-3,4-diethoxyhydrocinnamate was prepared 28.0 g. of the amino-hydroxy compound following the procedure outlined in Example l-A.

B. Preparation of 2,4-diamino compound from for l-B. From 20.0 g. of the amino-hydroxy compound was prep-ared 2.8 g. of the diamino compound melting at 185-188".

EXAMPLE 6 2,4-diamino-5-(3'4-dimethomy-(6 or 1 nitro) benzyl pyrimidine) To 3.0 g. of 2,4-cliamino-5-(34'-dimethoxybenzyl) -pyrimidine (described in Example 2) dissolved in 40 ml. of glacial acetic acid was added 2.16 ml. of nitric acid (sp. gr. 1.4) in 3 portions over /2 hour, with stirring, keeping the temperature at 15 C. The mixture was then stirred an additional hour at which point the temperature had risen to 30. The mixture was then poured over 300 g. of cracked ice and brought to pH 10 with concentrated ammonium hydroxide solution. After standing an hour the precipitate was filtered off and washed with cold water. The precipitate was then recrystallized from 95 percent ethanol in pale yellow needles melting at 200-203". The yield was 2.7 g.

EXAMPLE 7 2,4 diamino 5 (3' methoazy 4 propoxybeneyl) pyrimidine The aminohydroxy compound was prepared in the usual manner from ethyl-3-methoXy-4-propoxyhydrocinnamate. It was treated in the usual manner with phosphorous oxychloride followed by alcoholic ammonia to give the desired 2,4- diamino-5- (3'-methoxy-4' -propoxy) benzyl pyrimidine melting at 178-179.

EXAMPLE 8 2,4 diamino 5 (2' methoazy 5' chlorobenzyl) pyrimidine The aminohydroxy compound was prepared in the usual manner from ethyl-Z-methoxy-5-chlorohydrocinnamate. From 26 g. (0.11 mole) ester there was obtained '7 .0 g. of aminohydroxy pyrimidine melting at 278-284". From 6.0 g. of the aminohydroxy compound by the procedure outlined in Example 1-B there was obtained 3.2 g. of the desired 2,4-diamino-5-(2'-methoxy-5- chloro) benzyl pyrimidine melting at 169-171".

EXAMPLE 9 2,4-diamino-5- (3 4 -dimetho:ry-5 -bromobenzyl) pyrimidine From 24.0 g. (0.07 mol) of ethyl-3,4-dimethoxy-5-bromohydrocinnamate was prepared 16.0 g. of the desired aminohydroxy compound by the usual procedure. This compound (10 g.) was chlorinated and aminated in the usual manner to give 3.0 g. of the 2,4-diamino-5-(3'4'- dimethoxy-5-bromobenzyl) pyrimidine melting at 198-201.

EXAMPLE 10 2,4-diamino-S-p-phenylbenzylpyrimidine The aminohydroxy compound (20.0 g.) was prepared irom 23 g. of ethyl-p-phenyl-hydrocinnamate by the usual procedure. Fifteen grams of the aminohydroxy compound after treatment with phosphorous oxychloride followed by ammonia gave 8.0 g. of the desired 2,4-diamino-5-p-phenylbenzyl pyrimidine melting at 250-258".

Since the base is the physiologically active moiety in any non-toxic salt of any compound described herein, the known non-toxic salts of these derivatives are regarded as the equivalent of the uncombined bases described in the specifithe above followed the usual procedure outlined cation and claims herein.

5 We claim: 1. A compound of the formula radical, of chlorine, bromine and the nitro groups. 5

2. 2,4-diamino-5-(3'4-diethoxybenzyl) pyrimidine.

3. 2,4-diamino-5-(3'4'-dimethoxybenzyl) pyrimidine.

4. 2,4 diamino 5 (3' ethoxy 4' methoxybenzyl) pyrimidine.

5. 2,4 diamino 5-(3' methoxy 4' propoxybenzyl) pyrimidine.

6. 2,4 diamino 5(3'4 dirnethoxy 5 bro- 10 mobenzyl) pyrimidine.

GEORGE H. HITCHINGS. ELVIRA A. FALCO.

No references cited. 

1. A COMPOUND OF THE FORMULA 